BTK (Bruton's Tyrosine Kinase) is a type of TEC-family tyrosine kinase together with ITK (Interleukin-2 Tyrosine Kinase), RLK (Resting Lymphocyte Kinase) and BMX (Bone-Marrow tyrosine kinase gene on chromosome X), and BTK acts as a regulator of early B-cell development as well as of mature B-cell activation, signaling and survival.
The B-cell is signaled by a B cell receptor (BCR) that recognizes an antigen attached to the surface of an antigen-presenting cell and is activated into a mature antibody-producing cell. However, aberrant signaling via BCR leads to abnormal B-cell proliferation and the formation of pathologic autoantibodies, and thereby can induce cancer, autoimmune and/or inflammatory diseases.
Thus, in the abnormal B-cell proliferation, signaling via BCR may be blocked when BTK is deficient. Thus, inhibition of BTK can block B-cell mediated disease processes, and the use of BTK inhibitors may be a useful approach for the treatment of B-cell mediated diseases.
Furthermore, BTK can be expressed by other cells that may be associated with disease besides B-cells. For example, BTK is important components for Fc-gamma signaling in bone marrow cells, and is expressed by mast cells. Specifically, BTK-deficient bone marrow-induced mast cells exhibit impaired antigen-induced degranulation, and inhibition of BTK activity is known to be useful for treating pathological mast cell responses such as allergy and asthma (Iwaki et al. J. Biol Chem. 2005 280: 40261). In addition, it is known that monocytes from XLA patients, in which BTK activity is absent, show decreased TNF alpha production following stimulation and thus TNF alpha-mediated inflammation could be inhibited by BTF inhibitors (see, Horwood et al., J. Exp. Med. 197: 1603, 2003).
Therefore, there is a need in the art to develop BTK inhibitors capable of inhibiting the activity of BTK. As these BTK inhibitors, WO 2008/039218 discloses 4-aminopyrazolo[3,4-d]pyrimidinylpiperidine derivatives, and WO 2015/061247 discloses hetero compounds such as pyridine, pyrimidine, pyrazine and pyridazine, and WO 2014/055934 discloses pyrimidinyl phenyl acrylamide derivatives.
However, the developed BTK inhibitors show inhibitory activity against BTK as well as various other tyrosine kinases such as EGFR (Epidermal Growth Factor Receptor) and ITK, whereby they show side effects such as rash, diarrhea, arthralgias, myalgias, atrial fibrillation, ecchymosis, and major hemorrhage (see, Byrd J C et al. N Engl J Med 2013; 369:1278-9, Byrd J C et al. N Engl J Med 2014; 371:213-23 and O'brien S et al. Lancet Oncol 2014; 15:48-58). Therefore, selective inhibition of BTK activity is very important.
In view of the above, as a result of studying novel compounds, the present inventors has found that a compound having a chemical structure different from BTK inhibitors reported so far not only has excellent BTK activity inhibitory effect, but also has remarkably high selectivity for the inhibitory activity of BTK vs. ITK, thereby completing the present invention. The compounds belonging to the present invention mainly have BTK inhibitory activity on their own, but do not exclude a possibility of exhibiting a pharmacological action as an efficacious agent by a special body environment or by products of metabolic process, after absorption into the body.